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WO2018156560A1 - Compositions et méthodes pour la neuroprotection utilisant de l'argent nanoparticulaire - Google Patents

Compositions et méthodes pour la neuroprotection utilisant de l'argent nanoparticulaire Download PDF

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Publication number
WO2018156560A1
WO2018156560A1 PCT/US2018/018923 US2018018923W WO2018156560A1 WO 2018156560 A1 WO2018156560 A1 WO 2018156560A1 US 2018018923 W US2018018923 W US 2018018923W WO 2018156560 A1 WO2018156560 A1 WO 2018156560A1
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WO
WIPO (PCT)
Prior art keywords
site
injury
treatment
group
silver nanoparticles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2018/018923
Other languages
English (en)
Inventor
Johnson Yiu-Nam Lau
Michael Kai Tsun TO
Kenneth Man Chee Cheung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Avalon Nanosilver Rx (hk) Ltd
Original Assignee
Avalon Nanosilver Rx (hk) Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Avalon Nanosilver Rx (hk) Ltd filed Critical Avalon Nanosilver Rx (hk) Ltd
Priority to US16/487,733 priority Critical patent/US20210030789A1/en
Priority to EP18758118.6A priority patent/EP3585401A4/fr
Priority to CN201880026000.5A priority patent/CN111936151A/zh
Publication of WO2018156560A1 publication Critical patent/WO2018156560A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the field of the invention is prevention and/or treatment of neurological damage, particularly utilizing nanoparticulate metals.
  • TSCI is generally a result of traffic accidents, falls and sports injuries, and spinal cord damage during surgical procedures (for example, correction of spinal deformities).
  • the sudden trauma to the vertebral column produces primary injury that compresses and damages the spinal cord, disconnecting the communication channel between the brain and the body, causing functional problems like sensory loss, neuropathic pain, lifetime paralysis and even death.
  • the body responds to the injury with an inflammatory reaction that often results in a secondary injury.
  • Such inflammatory reaction can result in ischemia, edema, excitotoxicity, hypoxia, disturbances of ion homeostasis and apoptosis.
  • Silver nanoparticles i.e. particles of silver metal having a mean diameter of less than 1 ⁇
  • TGF- ⁇ and IL-6 which have been associated with scar formation
  • VEGF vascular endothelial growth factor
  • the inventive subject matter provides apparatus, systems and methods in which a preparation of silver nanoparticles (AgNPs), which can be provided as a hyaluronic acid containing gel, are applied to a site of central nervous system damage (for example, a spinal cord injury resulting from trauma due to accident and/or as a complication of spinal surgery) prior to, at the time of, or following trauma in order to reduce or prevent inflammation and aid in healing and recovery of function.
  • a site of central nervous system damage for example, a spinal cord injury resulting from trauma due to accident and/or as a complication of spinal surgery
  • Such AgNPs are found to modify the ratio between Ml and M2 phenotype macrophages, at least in part by selective killing of Ml phenotype cells.
  • compositions for use in treating an animal which can include a human
  • a pharmaceutical carrier in the form of a non-flowable gel.
  • the silver nanoparticles can have a mean diameter of less than about 1 ⁇ , such as from about 5 nm to about 20 nm.
  • the pharmaceutical carrier can include a biopolymer, such as a protein, a polysaccharide, a starch, and an aminoglycoside (e.g. hyaluronic acid).
  • the pharmaceutical carrier can include a stabilizing agent that reduces or prevents aggregation of the silver nanoparticles, such as polyvinylpyrrolidone.
  • FIGs. 2A and 2B show results of cell viability studies of original, unmodified phenotype RAW264.7 macrophages along withMl and M2 phenotypes of RAW264.7 macrophages treated with different concentrations of 5 nm to 20nm AgNPs on Day 2 and Day 3 of exposure, respectively. The selective killing effect of silver nanoparticles at concentrations of 20 ⁇ and greater is evident.
  • FIG. 4 schematically depicts a typical synthesis of an AgNPs-loaded hydrogel.
  • FIG. 5 schematically depicts the mechanism utilized for production of controlled contusion spinal cord injuries (SCI) in the studies described herein.
  • SCI controlled contusion spinal cord injuries
  • Inventors have surprisingly found that application of silver nanoparticles can modulate the M1/M2 ratio in acute inflammation, such as that following neurological trauma (e.g. spinal cord injury, stroke, etc.).
  • neurological trauma e.g. spinal cord injury, stroke, etc.
  • AgNPs can be selectively cytotoxic for certain cell types.
  • Inventors have identified differential effects of AgNPs on primary chondrocytes and rat chondrosarcoma (RCS) cells, where the cytotoxicity of AgNPs was found to be dose-dependent.
  • monoclonal antibodies directed to components of the immune system and/or inflammatory process.
  • examples include antibodies directed to Ml macrophages, interleukin 1, ⁇ -interferon, and/or TNFa.
  • Still other complementary therapeutic approaches include treatment with cytokines that favor an increased M2 component in the M1/M2 balance.
  • cytokines include interleukin 4, interleukin 10, and interleukin 13.
  • Silver nanoparticles (AgNPs) in suspension were synthesized using a chemical reduction method.
  • a 500 ml solution containing 0.7mM sodium citrate dihydrate (Sigma- Aldrich) and O.lmM silver nitrate (AgN0 3 ; Sigma- Aldrich) was bubbled and vigorously stirred under nitrogen for 30 minutes at room temperature.
  • NaBH 4 sodium borohydride
  • the FLS was designed to give a quick observational score that describes a forelimb' s functional capability during locomotion (87).
  • the categories of scoring system are based on behavioral changes observed after unilateral cervical injury, with a range from 0 (complete paralysis) to 17 (healthy condition). Rats were placed in an enclosure (5 cm x lm), allowing the animal to move freely. Left forepaw behaviors were recorded by digital video for further analysis by two blinded observers. Each rat performed the test trials 4 times at each time point after 1 or 2 warm-up practices.
  • FIGs. 11A and 11B show the results of
  • FIG. 11B shows typical results of similar immunofluorescent staining studies in which the primary antibody is directed to iNOS.
  • the mean intensity of fluorescence was quantified by software Image J. Values shown are means with standard deviation.
  • Wilson JR Fehlings MG. Riluzole for acute traumatic spinal cord injury: a promising neuroprotective treatment strategy.
  • KWO S YOUNG W
  • DECRESCITO V Spinal cord sodium, potassium, calcium, and water concentration changes in rats after graded contusion injury. Journal of neurotrauma.
  • Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. J Neuroinflammation.
  • Plesnila N Von Baumgarten L, Retiounskaia M, Engel D, Ardeshiri A, Zimmermann R, et al. Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-KB transcriptional activity. Cell Death & Differentiation. 2007;14(8): 1529-41.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physics & Mathematics (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Il s'avère qu'une préparation de nanoparticules d'argent est efficace pour améliorer la guérison fonctionnelle et comportementale d'une lésion traumatique de la moelle épinière. Les nanoparticules d'argent sont fournies dans un véhicule de type gel non fluide, duquel elles sont libérées avec une efficacité élevée, qui est appliqué localement à l'emplacement de la lésion de la moelle épinière. Il s'avère également que les préparations de nanoparticules d'argent décrites par les présentes modifient le rapport M1/M2 des phénotypes de macrophages et fournissent un effet synergique en combinaison avec de l'arginase pour favoriser des processus de cicatrisation à l'emplacement de la lésion traitée, réduisant l'inflammation post-traumatique.
PCT/US2018/018923 2017-02-22 2018-02-21 Compositions et méthodes pour la neuroprotection utilisant de l'argent nanoparticulaire Ceased WO2018156560A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US16/487,733 US20210030789A1 (en) 2017-02-22 2018-02-21 Compositions and methods for neuroprotection utilizing nanoparticulate silver
EP18758118.6A EP3585401A4 (fr) 2017-02-22 2018-02-21 Compositions et méthodes pour la neuroprotection utilisant de l'argent nanoparticulaire
CN201880026000.5A CN111936151A (zh) 2017-02-22 2018-02-21 利用纳米颗粒银的用于神经保护的组合物和方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762462145P 2017-02-22 2017-02-22
US62/462,145 2017-02-22

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WO2018156560A1 true WO2018156560A1 (fr) 2018-08-30

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US (1) US20210030789A1 (fr)
EP (1) EP3585401A4 (fr)
CN (1) CN111936151A (fr)
TW (1) TW201834667A (fr)
WO (1) WO2018156560A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230414656A1 (en) * 2022-06-28 2023-12-28 Panacea Spine, LLC Systems and methods for repairing spinal disc injury or treating spinal disc disease

Citations (2)

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KR20090080855A (ko) * 2008-01-22 2009-07-27 (주)네추럴에프앤피 항염증 효과를 갖는 금속 나노입자를 유효성분으로함유하는 염증질환 및 면역질환의 치료용 약학조성물
US20160015742A1 (en) * 2014-07-16 2016-01-21 Gnt Biotech & Medicals Corporation Transcranial burst electrostimulation apparatus and its applications

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US20050123526A1 (en) * 2003-12-01 2005-06-09 Medtronic Inc. Administration of growth factors for neurogenesis and gliagenesis
CN101766836B (zh) * 2009-01-21 2012-09-05 丁坦 纳米银脊髓及外周神经损伤修复材料的制备工艺
ES2688381T3 (es) * 2012-09-28 2018-11-02 Stelo Technologies Métodos para hacer nanopartículas de plata y sus aplicaciones

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
KR20090080855A (ko) * 2008-01-22 2009-07-27 (주)네추럴에프앤피 항염증 효과를 갖는 금속 나노입자를 유효성분으로함유하는 염증질환 및 면역질환의 치료용 약학조성물
US20160015742A1 (en) * 2014-07-16 2016-01-21 Gnt Biotech & Medicals Corporation Transcranial burst electrostimulation apparatus and its applications

Non-Patent Citations (4)

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Title
HU , XIAOMING ET AL.: "Microglial and macrophage polarization-new prospects for brain repair", NATURE REVIEWS NEUROLOGY, vol. 11, no. 1, January 2015 (2015-01-01), pages 56 - 64, XP055537625 *
HUANG, CHIN-LIN ET AL.: "Silver nanoparticles affect on gene expression of inflammatory and neurodegenerative responses in mouse brain neural cells", ENVIRONMENTAL RESEARCH, vol. 136, January 2015 (2015-01-01), pages 253 - 263, XP055537630 *
RAJA, MAMILLA R. CHARAN ET AL.: "ApAGP-fabricated silver nanoparticles induce amendment of murine macrophage polarization", JOURNAL OF MATERIALS CHEMISTRY B, vol. 5, no. 19, 6 February 2017 (2017-02-06), pages 3511 - 3520, XP055537632 *
See also references of EP3585401A4 *

Also Published As

Publication number Publication date
EP3585401A4 (fr) 2020-12-30
EP3585401A1 (fr) 2020-01-01
CN111936151A (zh) 2020-11-13
US20210030789A1 (en) 2021-02-04
TW201834667A (zh) 2018-10-01

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